5-Fraction Re-radiosurgery for Progression Following 8-Fraction Radiosurgery of Brain Metastases From Lung Adenocarcinoma: Importance of Gross Tumor Coverage With Biologically Effective Dose ≥80 Gy and Internal Dose Increase

The criteria for indication of salvage stereotactic radiosurgery (SRS) for local progression following multi-fraction (mf) SRS of brain metastases (BMs) remain controversial, along with the optimal planning scheme. Herein, we described a case of BMs from pan-negative lung adenocarcinoma (LAC), in which the two lesions of local progression following initial eight-fraction (8-fr) SRS were re-treated with 5-fr SRS with the biologically effective dose (BED10) of ≥80 Gy, based on the linear-quadratic (LQ) formula with an alpha/beta ratio of 10. The re-SRS resulted in the alleviation of symptoms and favorable tumor responses with minimal adverse effects during the 7.3-month follow-up. In the lesions of local progression, the gross tumor volume (GTV) coverage with 49.6 Gy (BED10 80 Gy) was generally insufficient, and the GTV dose wes relatively homogeneous with ≥87% isodose covering. In contrast, the 5-fr re-SRS was performed with sufficient GTV coverage with ≤68% isodose of 43 Gy (BED10 80 Gy). Taken together, sufficient GTV coverage with a BED10 of ≥80 Gy and steep dose increase inside the GTV boundary, that is, extremely inhomogeneous GTV dose, are important in 8-fr SRS for ensuring excellent local control of BMs from pan-negative LAC. For local progression following mfSRS that does not fulfill both criteria, re-SRS with the above planning scheme can be an efficacious and safe treatment option for at least six months, especially in cases in which the prior SRS was performed with a dose/fractionation under adequate consideration of brain tolerance. The BED10 seems to be the most suitable for estimating the anti-tumor efficacies of SRS doses in 3-8 fr, similar to that of a single fraction of 24 Gy.


Introduction
Stereotactic radiosurgery (SRS) is an essential local treatment option for non-miliary and non-disseminated brain metastases (BMs) from non-small cell lung cancer (NSCLC); however, its dose gradient outside and inside the tumor margin and dose fractionation remain highly variable among institutions [1,2]. In response to the target-volume limitation of single-fraction SRS regarding efficacy and safety, three-to five-fraction (3-5 fr) SRS is increasingly applied to ≥1.5-2 cm BM, for which 27-30 Gy in 3 fr and 30-35 Gy in 5 fr are common schedules [1,3,4]. The corresponding biologically effective doses (BED) that are based on the standard linear-quadratic formula with an alpha/beta ratio of 10 (BED 10 ) are approximately 50-60 Gy [5].
However, approximately 20% of local tumor progression generally occurs within one year when these dose fractionation schemes are used [1]. Meanwhile, Matsuyama et al. stated that 2-10 fr SRS with the BED 10 of ≥80 Gy prescribed to 90% isodose surface (IDS) covering 1-2 mm outside the gross tumor volume (GTV) boundary can improve local control of BMs from NSCLC; however, the one-year local control rate for >2 cm BMs was ≤85% [6]. Additionally, adverse radiation effects (AREs) generally increase significantly when the irradiated isodose volumes, including GTVs, receiving ≥20 Gy in 3 fr or ≥24 Gy in 5 fr exceed >20 cm 3 [3,7]. Therefore, volume effects should also be considered, even in multi-fraction (mf) SRS. In cases of more than four BMs and/or brainstem involvement, the prescription dose may be compromised, considering the increased risk of AREs. Furthermore, for radiographic local progression following a nadir response after SRS, the criteria for determining whether tumor regrowth or ARE predominates and re-SRS indication remain controversial, along with the optimal dose fractionation scheme and dose distribution for re-SRS [8,9].
Herein, we present a case of BMs from lung adenocarcinoma (LAC) harboring no common driver genetic alterations that were initially treated with 8-fr SRS without subsequent anti-cancer pharmacotherapy [10]. Despite the GTV coverage with the BED 10 of 80 Gy, four of the six BMs developed local progression. Two of the four lesions were re-irradiated with 5-fr SRS adopting sufficient GTV coverage with the BED 10 of 80 Gy and a steep internal dose increase (extremely inhomogeneous GTV dose). Through a description of the clinical course along with detailed analyses of the planning parameters for the initial and re-SRS, we discuss several relevant issues as follows: the optimal dose distribution of 8-fr SRS for ensuring long-term sustained local control, criteria for determining whether tumor regrowth or ARE predominates in local progression following SRS, indication and validity of re-SRS with a BED 10 of 80 Gy, and optimal BED formula for estimating anti-tumor efficacy in 3-8 fr SRS.
Part of this study was previously presented at the 30 th Annual Meeting of the Japanese Society for Stereotactic Radiosurgery, held online on June 11 to July 8, 2021.

Case Presentation
A 70-year-old, right-handed male who was an ex-smoker presented with unsteadiness and mild left-sided hemiparesis. Ten months earlier, the patient underwent left upper lobectomy with regional lymph node dissection for lung adenocarcinoma (LAC) detected by screening. Pathological examination revealed mediastinal lymph node metastases, negative for major genetic alterations, and programmed cell death ligand-1 (PD-L1) expression of 5-10%. The patient received four courses of adjuvant chemotherapy consisting of cisplatin and vinorelbine until four months before the onset of BMs. Magnetic resonance imaging (MRI) revealed six lesions compatible with BMs, and systemic examination revealed no obvious extracranial recurrences or metastases. The Lung-molGPA score proposed by Sperduto et al. was 1.5 (Karnofsky Performance Score: 80%, extracranial metastasis: absent) [11]. The neurological symptoms were mainly attributed to the two BMs located in the right thalamo-mesencephalon and the right superior parietal lobule (near the arcus parietooccipitalis). These six BMs were initially treated with SRS alone using CyberKnife (CK) M6 (Sunnyvale, CA: Accuray Inc.) with 6 MV x-rays [12].
Since 2018, to achieve longer-lasting tumor shrinkage and enhance long-term safety for BMs up to approximately 5 cm, we shifted to the dose prescription regimen of ensuring GTV coverage with BED 10 of ≥80 Gy along with versatile and flexible dose fractions ranging from 3 to 15 [5,8,[12][13][14]. Given the largest lesion volume, each localization (brainstem involvement), and the distance between lesions, ≥5 fr was deemed suitable for SRS of the present case [3,7]. Finally, 49.6 Gy in 8 fr was adopted for the GTV prescription dose to ensure long-term safety, considering the effects of dose interference due to the simultaneous irradiation of six lesions and the predicted prognosis of isolated central nervous system (CNS) metastases. The GTVs were defined as enhancing lesions that were nearly consistent with the visible masses on T2-weighted images (T1/T2 matching) [8,12]. The optimization algorithm for SRS planning was Sequential (Sunnyvale, CA: Accuray Inc.), built into the dedicated planning system Precision (Sunnyvale, CA: Accuray Inc.). Simultaneous and comprehensive optimization with a single path (plan) using 178 beams from 98 nodes was adopted to efficiently irradiate the six lesions in a short time, for which a regular dodecagon-shaped variable-sized collimator Iris (Sunnyvale, CA: Accuray Inc.) was leveraged [12]. The estimated treatment time (EST) was 39 minutes per fraction (mean 6.5 minutes per lesion). The dose distributions, dose-volume histograms, and MRIs before and after SRS for the three large lesions are shown in Figures 1A-1L    The planning parameters for the six lesions are included in Tables 1, 2. Although ≥98% GTV coverage with a BED10 of 80 Gy was the principle, the GTV coverage with 49.6 Gy in 8 fr was partially compromised as <98%, especially for the thalamo-mesencephalic lesion, considering the non-oligo BMs and the future high probability of new lesions in other intracranial sites. In addition, by selecting larger collimator sizes for Iris, shortening the irradiation time was prioritized over GTV coverage with ≤80% IDS. This was also performed before the installation of CK-VOLO (Sunnyvale, CA: Accuray Inc.) for the optimization algorithm [12]. Accordingly, the GTV doses were homogeneous, and the dose gradients outside the GTV boundary were gradual [2,15]. Regarding the inter-fractional tumor changes and/or displacement, no obvious shrinkage was observed, although enlargement of the partially cystic component and medial displacement of the tumor were observed in one case each ( Figures 4A-4L) [8,12,16].

Initial SRS (8 fr) Re-SRS (5 fr)
Tumor       Owing to anti-brain edema medication, followed by tumor shrinkage, the patient's neurological symptoms improved during SRS and almost disappeared within one month. After SRS, the patient was followed up without subsequent anti-cancer pharmacotherapy, considering isolated CNS failure. The anti-cancer treatments administered after the initial SRS are summarized in Table 3.  Thereafter, the size of the right parietal and thalamo-mesencephalic lesions gradually increased, and the patient experienced weakness and numbness in the left upper and lower extremities ( Figures 1A-1L, 3A-3L). Therefore, the right parietal lesion was completely removed 6.3 months after the initial SRS, using neuronavigation and intraoperative MRI under general anesthesia. The dominance of viable cancers was verified by pathological examination. Postoperative recovery was uneventful; however, the patient's numbness and weakness gradually progressed. MRI obtained 8.2 months after the initial SRS revealed further enlargement of the right thalamo-mesencephalic lesion ( Figures 3A-3L and Table 1), obvious enlargement of the right frontal lesion (Figures 2A-2L and Table 1), two limited locally recurrent lesions in the post-resection cavity (image not shown), and two new lesions ( Table 2). The dose distribution design for the initial 8-fr SRS, which mostly resulted in PRs followed by regrowth, is shown in Figures 5A, 5B.  Figure  5A, 5B). Considering the local progression after initial SRS with 49.6 Gy covering 98.4% of the GTV in the right frontal lesion, we determined the necessity of a higher therapeutic intensity to make re-irradiation effective (Figures 2A-2L). Specifically, sufficient GTV coverage with the BED 10 of 80 Gy, sufficient increase in the GTV internal dose, steeper dose gradient outside the GTV boundary, and smaller number of fractions were deemed appropriate for re-SRS. A total of six lesions, including the two lesions of local progression following initial SRS, were treated with a third SRS using the GTV marginal dose of 43 Gy in 5 fr using CK with 192 beams from 78 nodes ( Figures 6A-6L, 7A-7L, 8A-8N, and Tables 1, 2). The EST was 45 minutes per fraction (mean 7.5 minutes per lesion). After completion of the third SRS, systemic re-examination revealed metastases to the thoracic spine. Chemoimmunotherapy consisting of carboplatin, paclitaxel, bevacizumab, and atezolizumab (ABCP) was initiated 8.6 months after the initial SRS, and three courses were administered [17]. The patient's neurological symptoms, which were mainly attributed to the local progression of the right thalamo-mesencephalic lesion, gradually improved after the third SRS. The two re-irradiated lesions showed favorable both clinical and radiographic responses ( Figures   6A-6L, 7A-7L). The two newly manifested lesions of 0.66 cm 3 and 0.40 cm 3 showed complete responses (CRs) without subsequent progression during the 7.3-month imaging follow-up ( Table 2 and Figures 8A-8N).
Eleven months after the initial SRS, a fourth 5-fr SRS was required to salvage two limited meningeal disseminations in the right occipital lobe near the resection cavity (data not shown). However, 12 months after the initial SRS, the patient was transferred to palliative care because of declining performance status. Although non-CE MRI 15.7 months after the initial SRS showed controlled intracranial metastases, continued analgesia and sedation for cancer-related pain were required. The patient died 18.8 months after the initial SRS.
The serial MRIs that were observed for more than one year after SRS were retrospectively reviewed for evaluating the dose-response relationships in the nine small BMs of ≤0.25 cm 3 ( Table 2). Only one of nine lesions had poor local control: the right frontal lesion (0.13 cm 3 ) treated with 8-fr SRS resulted in PR followed by smoldering, in which the GTV minimum dose (D min ) was 48.9 Gy (BED 10 78.8 Gy) with 91.2% IDS, and the GTV coverage with 49.6 Gy was 93% (Figures 8A-8N). The other two smaller lesions resulted in CRs, in which the GTV D min was 49.0 Gy (BED 10 79.0 Gy) with 91.8% IDS ( Table 2). Meanwhile, all six BMs Thus, the durations with the GTV coverage of 70%, 93%, 97%, and 98% were 2.8 ( Figures 3A-3L), 8.2 ( Figures  8A-8N), 4.5 ( Figures 1A-1L), and 8.2 months (Figures 2A-2L), respectively. Hence, a lower GTV coverage with 49.6 Gy tended to shorten the time to local progression, especially for >0.7 cm 3 BMs.
As BEDs and corresponding absolute doses vary depending on the model formula and an alpha/beta ratio, the difference and variation in the BEDs and corresponding multi-fraction physical doses that are equivalent to a single fraction of 24 Gy are shown in Table 4. A single fraction of 24 Gy generally yields approximately 95% one-year local tumor control probability [1,7,14].

Discussion
Despite the relatively high baseline prescription dose of 49.6 Gy (BED 10 80 Gy) to the GTV, in addition to mostly sufficient coverage of 40 Gy (BED 10 60 Gy) to 2 mm outside the GTV boundary, the initial 8-fr SRS resulted in local control failures in the four lesions (67%), including even a small lesion of 0.13 cm 3 . As mentioned above, the GTV coverage with 49.6 Gy was <98%, except in one lesion, and the D max was ≤57 Gy (BED 10 <100 Gy). The relatively homogeneous GTV doses resulted in no obvious tumor shrinkage during 8-fr SRS, whereas partial cystic enlargement and tumor displacement relative to the cranium inevitably led to dose falloff in parts of each tumor boundary [8,12,16]. In addition, a lower GTV coverage with 49.6 Gy shortened the time to local progression. Meanwhile, the two lesions of <0.1 cm 3 with a D min of ≥49 Gy were well controlled. The difference in local control may be attributed to differences in tumor cell numbers and internal radioresistance compared to those in larger lesions. Given that GTV coverage with ≤80% IDS of 53 Gy in 10 fr (BED 10 81 Gy) can improve local control for BMs >10 cm 3 , the local control failures in 8-fr SRS were mainly attributed to insufficient doses to both the margin and interior of the GTVs [5]. In addition to adequate coverage of a GTV boundary with 49.6 Gy, steep dose increase inside the GTV boundary with at least <80% IDS coverage would be important for long-term local control in 8-fr SRS. The anti-tumor efficacy of ≥49.6 Gy in 8 fr may be similar to that of a single fr of 24 Gy with a one-year tumor control probability of 95% [1]. In this respect, among the various formulae and alpha/beta ratios, the linear-quadratic (LQ) modelbased BED 10 seems to be the most suitable for predicting similar anti-tumor efficacies of single-and 8-fr SRS ( Table 4). Furthermore, to ensure BED 10 -based GTV dose heterogeneity equivalent to that of a single fraction of 24 Gy with 80% IDS covering (D max 30 Gy, BED 10 120 Gy), ≤75% IDS covering with 49.6 Gy in 8 fr would be suitable ( Figure 5B and Table 5).   The BMs of ≤0.25 cm 3 treated with ≥89% IDS to the D min of ≥35 Gy in 3 fr (BED 10 ≥76 Gy) were well controlled ( Table 2). Thus, for small lesions, a 3-fr dose based on BED 12 or BED 10 may provide an efficacy similar to that of a single fraction of 24 Gy ( Table 4). The BMs of 0.40 cm 3 and 0.66 cm 3 with ≤77% IDS to the D min of ≥43 Gy in 5 fr (BED 10 ≥80 Gy) were also well controlled ( Table 2 and Figures 8A-8N). The maximum responses of CRs may be enhanced with chemoimmunotherapy initiated immediately after the completion of 5-fr SRS. Taken together, the elementary LQ model-based BED 10 may be the most suitable for estimating the anti-BM efficacies of 3-, 5-, and 8-fr SRS doses, which are similar to those of a single fraction of 24 Gy. GTV coverage with a BED 10 of ≥80 Gy in 1-10 fr generally seems to be important for ensuring excellent local control. Furthermore, a BED 10 of ≥81.6 Gy may be suitable to rigorously ensure similar efficacy to a single fraction of 24 Gy ( Table 5). If consistent GTV coverage using a BED 10 of 80 Gy with 80% IDS is used, regardless of the number of dose fractions, the BED 10 in the GTV center decreases as the number of fractions increases ( Table 5). Therefore, the larger the number of dose fractions, the more inhomogeneous the GTV dose should be designed ( Table 5).

Variables
In the present case, we had to manage the challenging issue of re-irradiation for recurrences after 8-fr SRS with the BED 10 of 80 Gy to the GTVs. To render re-irradiation clinically beneficial, sufficient alleviation of the relevant mass effect, that is, early and sufficient tumor shrinkage, is required; nevertheless, palliative and conservative doses are commonly used for re-irradiation with SRS [9]. Although the imaging and clinical follow-up periods after re-SRS were limited to 7.3 and 10.4 months, respectively, the 5-fr re-SRS with sufficient GTV coverage of 43 Gy and ≤68% IDS covering resulted in favorable responses both clinically and radiologically. Eight fractions of the initial SRS may render the surrounding brain immune to a significant ARE after re-SRS with the high BED 10 . Bevacizumab, which was included in chemoimmunotherapy, could also attenuate AREs; however, mild radiation-induced edema appeared only in the right frontal lobe after discontinuation ( Figures 6A-6L, 7A-7L) [18]. Taken together, the criteria for determining the dominance of tumor regrowth and indication for re-SRS may include the following: insufficient GTV coverage (<98%) with a BED 10 of 80 Gy, relatively homogeneous GTV doses, and dose/fractionation selection with adequate consideration of brain tolerance and volume effects in prior mfSRS, in addition to progression with T1/T2 matching.
Appropriate design and implementation of an initial SRS are important and should be prioritized to avoid re-treatment. Throughout the course of the present case, we renewed our recognition of the following: maximum response of PR indicates a residual viable tumor that will eventually regrow unless controlled with anti-cancer pharmacotherapy; thus, PR, especially within several months after SRS, does not guarantee excellent treatment [8]. Aside from LAC harboring major genetic alterations, for which low-dose SRS and molecular-targeted drugs are effective [19,20], complete tumor necrosis, including potential microscopic brain infiltration, should be aimed at achieving long-term sustained tumor control, especially in squamous cell carcinoma and pan-negative LAC, similar to the present case [8].
In isolated and symptomatic BMs, early symptom relief is necessary, and SRS is frequently initiated without determination of anti-cancer pharmacotherapy or its concurrent use, as in the present case. Subsequent anti-cancer medications can enhance anti-BM efficacies and mitigate potential AREs. The significance of anti-cancer pharmacotherapy and its appropriate selection after SRS of isolated BMs from pan-negative LAC remain issues for future investigation. In addition, the brain tolerance for 8-10 fr SRS, that is, dose-volume parameters relevant to symptomatic brain radionecrosis, remains a subject for further investigation [5].

Conclusions
Sufficient GTV coverage with a BED of ≥80 Gy and steep dose increase inside the GTV boundary (extremely inhomogeneous GTV dose) are important in 8-fr SRS for ensuring excellent local control of BMs from pannegative LAC. For local progression following mfSRS that does not fulfill both criteria, re-SRS with the above planning scheme can be an efficacious and safe treatment option for at least six months, especially in cases in which the prior SRS was performed with dose/fractionation selection under adequate consideration of brain tolerance. The elementary BED 10 seems to be the most suitable for estimating the anti-tumor efficacies of SRS doses in 3-8 fr, similar to that of a single fraction of 24 Gy.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI, Grant-in-Aid for Scientific Research with the grant number JP21K07561. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.